Compositions and methods for treating male infertility

Abstract

Methods, uses, and compositions for use in the treatment of infertility in male patients are described, including rFSH comprising [alpha] 2, 3-and [alpha] 2, 6-sialylation.

Description

[0001] The present invention relates to pharmaceutical products and methods for treating infertility in male patients. Background Art

[0002] Infertility affects approximately 15% of couples worldwide, with male infertility estimated to account for around 50% of cases. (Agarwal et al., Reprod Biol Endocrinol 13, 37 (2015)). However, in up to 40% of male infertility cases, the cause of the infertility cannot be determined; many of these cases lead to a diagnosis of idiopathic infertility. (Sabanegh et al., Male infertility in Campbell-Walsh urology 10th ed. (Campbell et al., eds.) (Saunders Elsevier, 2012) 616-647). Idiopathic male infertility (also known as idiopathic oligoasthenoteratozoospermia) generally refers to an unexplained reduction in sperm quality.

[0003] FSH has been used for many years to treat female infertility, both to stimulate ovulation, allowing conception to occur naturally or after intrauterine insemination, and to induce the growth of multiple follicles to obtain enough oocytes for assisted reproductive technology (ART). Recombinant FSH (rFSH) products approved for ovarian stimulation include follicle-stimulating hormone alfa ( Merck Serono / EMD Serono) and follitropin beta ( Merck & Co. / Schering-Plough (MSD / Schering-Plough), which is derived from the Chinese hamster ovary (CHO) cell line. The applicant has developed human cell line derived rFSH (follicle stimulating hormone delta, also known as FE 999049), which is the subject of international patent application number PCT / GB 2009 / 000978 published as WO 2009 / 127826 A. The European Commission (EC) granted (follitropin delta) for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technology (ART), such as an in vitro fertilization (IVF) cycle or an intracytoplasmic sperm injection (ICSI) cycle. It is the first human cell line derived cell lines). The (Follitropin Delta) product is produced by the method disclosed in International Patent Application No. PCT / GB 2009 / 000978.

[0004] However, there is a need for improved treatment of infertility in men, particularly men with idiopathic infertility, to improve their female partners' chances of spontaneous pregnancy. There is also a need for improved treatment of male factor infertility, testosterone deficiency in male patients, and idiopathic oligospermia. Summary of the invention

[0005] Given the key role that FSH plays in spermatogenesis, the pharmaceutical products and methods described herein rely on the therapeutic value of rFSH, including α2,3-sialylated and α2,6-sialylated, in the treatment of infertile men, particularly men with idiopathic infertility. Thus, disclosed herein is the use of rFSH, including α2,3-sialylated and α2,6-sialylated, as an alternative treatment to the current standard method, intracytoplasmic sperm injection (ICSI), for increasing sperm production in male infertility patients.

[0006] A meta-analysis of previous controlled clinical trials of FSH treatment in men with idiopathic infertility reported that recombinant When men were treated with FSH or urine-derived FSH, pregnancy rates improved both spontaneously and after ART (Santi et al., Endocr Connect. 2015;4:R46-58). However, study heterogeneity, high risk of bias, and lack of precise criteria for selecting the group most likely to respond to treatment limited the power of the authors' conclusions and highlight the need for further research in this area, including clinical trials to determine who will and will not respond to FSH treatment.

[0007] A recent meta-analysis evaluating the effects of FSH treatment on sperm parameters concluded that high FSH doses (700-1050 IU / week) increased sperm concentration, total sperm count, and forward motility, whereas lower FSH doses (up to 262.5 IU / week) only increased sperm motility, and moderate FSH doses (350-525 IU / week) increased sperm concentration with only a trend toward increased sperm count and motility (Canarella et al., Asian J Androl. 2020; 22:30916). The reported analysis did not identify different efficacy between urine-derived FSH and recombinant FSH.

[0008] Results of a dose-ranging trial in 354 men concluded that sperm counts in men with idiopathic oligospermia treated with the FSH product urofollicle stimulating hormone for injection (Livzon Pharmaceutical Group Co., Ltd., Zhuhai, China) were significantly increased when treated with at least 200 IU every other day, with these results first observed at the beginning of the third month of treatment (Ding et al., Clin Endocrinol. 2015; 83: 866-71). Improvements in sperm morphology and forward motility were reported at the beginning of the fifth month of treatment, and administration of 300 IU every other day for 5 months was reported to significantly improve spontaneous pregnancy rates and ART pregnancy rates. Although the authors refer to FSH as "recombinant FSH" and "rFSH", it is believed that the identified FSH product (urofollicle stimulating hormone for injection) actually used in the study was purified urine-derived FSH, not a recombinant product.

[0009] In this context, the inventors believe that compared with placebo, treating men with 11-13 μg daily doses of rFSH (e.g., 12 μg FE 999049) including α2,3-sialylated and α2,6-sialylated will effectively treat idiopathic infertility to increase the chance of spontaneous pregnancy observed in their female partners. The inventors also believe that this dosing regimen will effectively treat male factor infertility, testosterone deficiency in male patients, and idiopathic oligospermia. The treatment can also effectively improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or effectively reduce seminal DNA fragmentation of sperm / semen of treated male patients. Compared with men treated with placebo (inactive treatment), the treatment can also effectively increase the chance of positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects. The treatment may also be effective in reducing time to spontaneous pregnancy (as may be assessed, for example, by one or more of calendar time and number of menstrual cycles) in the female partners of the treated subjects compared to males treated with placebo.

[0010] This dosing regimen provides a higher dose of FSH than previously used (e.g., greater than the dosing regimen of 300 IU FSH every other day reported in Ding), and involves more frequent dosing (i.e., daily dosing). Thus, the dosing regimen described herein will result in increased FSH exposure. Although FSH has been shown to act in a dose-dependent manner in other settings (e.g., in the treatment of female infertility), the effects of such high daily dosing in males have not been previously studied. For example, although the pituitary gland releases FSH in a pulsatile manner, the effect of daily FSH dosing to produce relatively stable FSH serum concentrations in males has not been reported.

[0011] In females, follicle-stimulating hormone alpha at 150 IU / day corresponds to 10 μg / day of FE 999049 (Arce et al., RBMO. 2020;41(4):616-22). Thus, the inventors believe that a daily dose of, for example, 12 μg of FE 999049 described herein will provide an exposure level that is 20% higher than the previously evaluated dose of 300 IU every other day, i.e., the dosing regimen described herein will provide an exposure equivalent to approximately 180 IU / day.

[0012] The inventors also believe that the daily dosing described herein will result in less fluctuation in serum FSH concentration (i.e., more consistent exposure) than treatment every other day for two reasons: first, rFSH including α2,3-sialylation and α2,6-sialylation, such as the human cell line-derived FSH product FE99049, has a lower clearance rate than the CHO cell-derived product; and second, daily administration is expected to smooth out the fluctuations compared to, for example, administering two doses every other day. However, as noted above, the pituitary gland releases FSH in a pulsatile manner, and the effects of more stable FSH dosing in males have not been reported.

[0013] On the other hand, it is believed that supraphysiological FSH levels in males are safe and well tolerated because FSH acts only via specific FSH receptors (FSHR) in Sertoli cells of the testis (Simoni et al., Andrology 2020;8(3):535-44). In addition, to date, no evidence of FSHR downregulation in response to FSH stimulation has been reported, and no direct role of FSH in human bone turnover or metabolic function has been identified.

[0014] Based on the foregoing, proof of concept (PoC) clinical trials are described below. About the chance of spontaneous pregnancy observed in its female partner compared with placebo, clinical trials will use the daily dosage of 11-13 μ g FE 999049 (e.g., 12 μ g FE 999049) for 6 months to evaluate the treatment of the male with idiopathic infertility. Although not wishing to be bound by theory, for reasons including the above overview, the inventors believe that, compared with placebo, the use of the dosage regimen described herein including α2,3-sialylated and α2,6-sialylated rFSH will effectively improve the chance of spontaneous pregnancy observed in its female partner. For example, the inventors believe that the result of the clinical trial will prove that the daily dosage of 11-13 μ g FE999049 (e.g., 12 μ g FE 999049) will provide a significantly larger FSH exposure level than provided by daily administration of conventional (e.g., CHO cell derived) rFSH. The inventors also believe that the dosing regimen comprising α2,3-sialylated and α2,6-sialylated rFSH (e.g., FE 999049) described herein will produce fluctuations in serum FSH levels less than treatment with 300 IU FSH every other day (e.g., the dosing regimen reported in Ding 2015, supra). Therefore, although Ding reported the efficacy of its 300 IU FSH every other day regimen, the inventors believe that the dosing regimen comprising α2,3-sialylated and α2,6-sialylated rFSH (e.g., FE 999049) described herein may prove to be more effective. In addition, the inventors believe that a daily dose of 11-13 μg of α2,3-sialylated and α2,6-sialylated rFSH (e.g., 12 μg FE 999049) will be safe and well tolerated in male patients.

[0015] Therefore, the inventors believe that compared with placebo, the dosing regimen described herein can improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. The inventors also believe that this dosing regimen will effectively treat male factor infertility, testosterone deficiency in male patients and idiopathic oligospermia. The treatment can also effectively improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. Compared with males treated with placebo, the treatment can also effectively improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of the treated subject. Compared with males treated with placebo, the treatment can also effectively reduce the time to spontaneous pregnancy of the female partner of the treated subject (as can be evaluated, for example, by one or more of calendar time and menstrual cycle number).

[0016] Most of the studies on FSH treatment for improving sperm parameters have a treatment period of at least 3 months. See, for example, Ding, supra. This is because it is estimated that a complete spermatogenic cycle requires 60-70 days. See, for example, Heller, Science, 140: 184-86 (1963). And it is estimated that the time of transportation in the catheter system also requires 20-30 days. See, for example, Shaw's Textbook of Gynaecology, page 201 (Padubidri and Daftary ed.) (15th edition, 2011). However, emerging evidence shows that these time periods may be shorter. Therefore, the inventors believe that treatment as described herein can show therapeutic effects in a shorter time period, such as 30 days or a month (e.g., a medical month of 28 days). Therefore, in some aspects, treatment as described herein has a treatment period of 28 days, 30 days, a month or longer, as further discussed below.

[0017] According to some aspects, compositions comprising rFSH are provided for use in treating idiopathic infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is used to be administered to the patient at a daily dose of 11-13 μg (e.g., 12 μg). The infertility can be at least one sperm-related infertility selected from the following: azoospermia, oligospermia, asthenozoospermia, teratozoospermia, parvisemia, spermatopenia, and sperm abnormalities. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0018] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0019] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0020] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0021] According to some aspects, compositions comprising rFSH are provided for use in treating infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg). The infertility may be at least one sperm-related infertility selected from the following: azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, sperm cell reduction and sperm abnormality. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0022] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0023] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0024] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0025] According to some aspects, compositions comprising rFSH are provided for use in treating male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg). The infertility may be at least one sperm-related infertility selected from the following: azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, sperm cell reduction and sperm abnormality. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0026] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0027] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0028] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0029] According to some aspects, compositions comprising rFSH are provided for use in treating testosterone deficiency in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is used to be administered to the patient at a daily dose of 11-13 μg (e.g., 12 μg). In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0030] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0031] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0032] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0033] According to some aspects, compositions comprising rFSH are provided for use in treating idiopathic oligospermia in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is used to be administered to the patient at a daily dose of 11-13 μg (e.g., 12 μg). In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0034] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0035] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0036] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0037] According to some aspects, a method for treating infertility in a male patient, including idiopathic infertility and male factor infertility, is provided, the method comprising: administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg (e.g., 12 μg) / day. The infertility may be one or more sperm-related infertility disorders selected from the following: azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, sperm cell reduction, and sperm abnormality. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0038] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0039] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL. Additionally or alternatively, in some aspects, the patient has a baseline total sperm count of 5 million to 39 million. Additionally or alternatively, in some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. Additionally or alternatively, in some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, such as less than or equal to 2 million sperm / mL, such as less than or equal to 1 million sperm / mL, such as less than or equal to 500,000 sperm / mL. Additionally or alternatively, in some aspects, the patient has a total active sperm count of 5 million to 16 million. Additionally or alternatively, in some aspects, the patient has ≥15% of sperm with normal morphology (oval head, intact midsection and uncoiled single tail, and able to swim well and in a straight line). Additionally or alternatively, in some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. Additionally or alternatively, in some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. Additionally or alternatively, in some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not make his partner pregnant. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0040] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0041] According to some aspects, a method for treating testosterone deficiency in a male patient is provided, the method comprising: administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg (e.g., 12 μg) / day. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, e.g. Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0042] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0043] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2 In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0044] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0045] According to some aspects, a method for treating idiopathic oligospermia in a male patient is provided, the method comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg (e.g., 12 μg) / day. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase Cell lines.

[0046] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 4 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 5 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is applied to the patient for at least six months of treatment period (including a treatment period of at least one year).

[0047] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. In some aspects, the patient has ≤35 kg / m 2 In some aspects, the patient has a body mass index (BMI) of ≥1.4 mL of semen volume. In some aspects, the patient has a baseline total sperm count of 5 million to 39 million. In some aspects, the patient has a sperm concentration of less than 5 million sperm / mL. In some aspects, the patient has a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. In some aspects, the patient has a total active sperm count of 5 million to 16 million. In some aspects, the patient has a sperm with a normal morphology of ≥15% (oval head, complete midsection and uncoiled single tail, and can swim well and in a straight line). In some aspects, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some aspects, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some aspects, the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0048] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0049] Therefore, a composition comprising rFSH is provided, which is used for treating the idiopathic infertility of male patients, wherein the rFSH includes α2,3-sialylation and α2,6-sialylation, wherein the rFSH is used to apply to the patient with a daily dose of 11-13 μg (e.g., 12 μg). In addition, a composition comprising rFSH is provided, which is used for treating the infertility of male patients, wherein the rFSH includes α2,3-sialylation and α2,6-sialylation, wherein the rFSH is used to apply to the patient with a daily dose of 11-13 μg (e.g., 12 μg). In addition, a composition comprising rFSH is provided, which is used for treating the male factor infertility of patients, wherein the rFSH includes α2,3-sialylation and α2,6-sialylation, wherein the rFSH is used to apply to the patient with a daily dose of 11-13 μg (e.g., 12 μg). In addition, a composition comprising rFSH is provided, the composition is used for use in treating testosterone deficiency in male patients, wherein the rFSH includes α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is used to administer to the patient at a daily dose of 11-13 μg (e.g., 12 μg). In addition, a composition comprising rFSH is provided, the composition is used for use in treating idiopathic oligospermia in male patients, wherein the rFSH includes α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is used to administer to the patient at a daily dose of 11-13 μg (e.g., 12 μg). A method for treating infertility in a male patient, including male factor infertility and / or idiopathic infertility, is provided, the method comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day. In addition, a method for treating testosterone deficiency in a male patient is provided, the method comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day. In addition, a method for treating idiopathic oligospermia in a male patient is provided, the method comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day.

[0050] According to any of the foregoing, the infertility may be at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, spermatopenia and sperm abnormality.

[0051] According to any of the foregoing, 5% to 20% of the total sialylation may be α2,6-sialylation and / or the rFSH may be in produced or expressed in a cell line.

[0052] According to any of the foregoing, the daily dose of 11-13 μg (e.g., 12 μg) administered to the patient can be continued for a treatment period selected from: (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks, (xx) 24 weeks, and (xxi) 6 months.

[0053] According to any of the foregoing, the patient may have one or more or all of the following characteristics, for example, before treatment: body mass index (BMI) ≤ 35 kg / m 2 ; semen volume ≥ 1.4 mL; baseline total sperm count of 5 million to 39 million; sperm concentration of less than 5 million sperm / mL; sperm concentration of less than or equal to 3 million sperm / mL, such as less than or equal to 2 million sperm / mL, such as less than or equal to 1 million sperm / mL, such as less than or equal to 500,000 sperm / mL; total motile sperm count of 5 million to 16 million; ≥ 15% of sperm with normal morphology (oval head, intact midpiece and uncoiled single tail, and able to swim well and in a straight manner); baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L; baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L; baseline serum hormone concentration of testosterone of ≥ 300 ng / dL (equal to ≥ 10.4 nmol / L).

[0054] According to any of the foregoing, the treatment can be effective to increase the chance of spontaneous pregnancy in the female partner of the treated male patient. Additionally or alternatively, according to any of the foregoing, the treatment can be effective to improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or effectively reduce seminal DNA fragmentation of sperm / semen of the treated male patient. Additionally or alternatively, according to any of the foregoing, the treatment can be effective to increase the chance of a positive beta-human chorionic gonadotropin (βhCG) urine test in the female partner of the treated subject compared to men treated with a placebo. Additionally or alternatively, according to any of the foregoing, the treatment can be effective to reduce the time to spontaneous pregnancy in the female partner of the treated subject compared to men treated with a placebo. DETAILED DESCRIPTION

[0055] The proof of concept (PoC) trial described below will demonstrate the efficacy of the therapeutic products and methods described herein. The inventors believe that, compared with men treated with placebo, after treatment with a daily dose of 11-13 μg FE 999049 (e.g., 12 μg FE 999049), the chance of observing spontaneous pregnancy in a male with idiopathic infertility in his female partner will increase. The treatment can also effectively improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / semen of treated male patients. Compared with men treated with placebo, the treatment can also effectively increase the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of the treated subject. Compared with men treated with placebo, the treatment can also effectively reduce the time to spontaneous pregnancy of the female partner of the treated subject (as can be evaluated, for example, by one or more of calendar time and number of menstrual cycles).

[0056] As described above, the treatment effect can be observed before the end of the 6-month study treatment period. In addition, the patient's treatment benefit can last for a period of time after the treatment is stopped, so the trial will track the results after the end of the 6-month study treatment period, such as tracking 3 months after the end of treatment.

[0057] Thus, provided herein are treatments and dosage regimens constructed for treating male patients suffering from infertility, including idiopathic infertility and male factor infertility, and also for treating male testosterone deficiency and idiopathic oligospermia.

[0058] definition

[0059] Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art of assisted reproductive technology to which the present invention belongs. Reference is made herein to various methods known to those of ordinary skill in the art. Any suitable materials and / or methods known to those of ordinary skill in the art may be used to implement the present invention, according to the guidance provided herein. However, specific materials and methods are described. Unless otherwise stated, the materials, reagents, etc. referenced in the following description and examples may be obtained from commercial sources.

[0060] It should be understood that any definitions and terms defined herein are intended to have the same meaning and intent in any aspects and embodiments of the present invention unless expressly stated otherwise.

[0061] As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless explicitly stated to refer to the singular only.

[0062] As used herein, the term "about" means that as will be understood by one of ordinary skill in the art, depending on the context in which a number or range is used, the number or range so modified is not limited to the exact number or range shown, but encompasses ranges around the stated number or range. Unless otherwise apparent from the context or custom in the art, "about" means up to plus or minus 10% of the particular term.

[0063] As used herein, a "spontaneous pregnancy" is defined as a viable pregnancy (at least one intrauterine gestational sac with a fetal heartbeat documented by ultrasound).

[0064] As used herein, "ongoing pregnancy" refers to a pregnancy with a viable fetus and a detectable fetal heartbeat at 10-11 weeks of gestation, such as 8-9 weeks after blastocyst / embryo transfer.

[0065] As used herein, "clinical pregnancy" refers to pregnancy and detectable fetal heartbeat at 5-6 weeks of gestation, such as 3-4 weeks after blastocyst / embryo transfer.

[0066] In the treatments, methods and uses described herein, administration of rFSH begins on "Day 1" of treatment and can continue for 6 months or longer; for example, treatment can continue for 1, 2, 3, 4, 5 or 6 months, as discussed in more detail below.

[0067] As used herein, the term "spermatogenesis" refers to the production or development of mature sperm.

[0068] As used herein, the term "azoospermia" refers to a condition in which there are no measurable sperm in the ejaculate. As used herein, the term "oligospermia" refers to a condition in which the sperm concentration in the ejaculate is low, such as a condition in which there are less than 15 million sperm / mL of semen. As used herein, the term "asthenospermia" refers to a condition in which sperm has poor motility, such as a condition in which the motility is less than 40%. As used herein, the term "teratozoospermia" refers to a condition in which sperm has a large amount of abnormal morphology, wherein the normal morphology is defined as an oval head, a complete midsection, and an uncoiled single tail, and is able to swim well and in a straight line. As used herein, the term "microspermia" refers to a condition in which a male has a low ejaculate volume, such as a condition in which there are less than 2mL or less than 1.5mL. As used herein, the term "sperm cell reduction" refers to a decrease in sperm count relative to normal levels.

[0069] The terms "patient" and "subject," as well as "male" and "man," are used interchangeably herein.

[0070] In some aspects, the patient has the following BMI before treatment, for example, at the beginning of treatment or within about 90 days of treatment. The subject can have BMI>15 and BMI<40kg / m2, for example, BMI>17.5 and BMI<38kg / m2, for example, BMI>18 and BMI<25kg / m2, for example, BMI>20 and BMI<25kg / m2. Therefore, the product or method as described herein can be used to treat patients with BMI>15 and BMI<40kg / m2, for example, subjects with BMI>17.5 and BMI<38kg / m2, for example, subjects with BMI>18 and BMI<25kg / m2, for example, subjects with BMI>20 and BMI<25kg / m2 infertility. Therefore, the product or method as described herein can be used to treat subjects with BMI>17.5 and BMI<32kg / m2 infertility. BMI can be measured by methods well known in the art to identify patients for treatment.

[0071] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equivalent to ≥10.4 nmol / L).

[0072] These selection criteria are designed to identify the patient who most likely benefits from treatment as herein described.For example, FSH, LH and testosterone parameters can cover the patient with the gonadotropin level in the normal lower side.FSH, LH and testosterone threshold values ​​can exclude the patient suffering from low gonadotropin hypogonadism, and these patients will not be well treated by independent FSH treatment.On the other hand, the upper limit of FSH and LH parameters can exclude the patient with normal high to too high level of gonadotropin, its idiopathic infertility may have the patient of non-gonadotropin etiology and the patient that the therapeutic efficacy of FSH (if any) may be difficult to detect.

[0073] Thus, at the time of treatment, including at the start of treatment (including within about 90 days of starting treatment), the patient may have one or more or all of the following characteristics: Body mass index (BMI) ≤ 35 kg / m 2; semen volume ≥ 1.4 mL; baseline total sperm count of 5 million to 39 million; sperm concentration of less than 5 million sperm / mL, such as less than 4 million sperm / mL; sperm concentration of less than or equal to 3 million sperm / mL, such as less than or equal to 2 million sperm / mL, such as less than or equal to 1 million sperm / mL, such as less than or equal to 500,000 sperm / mL; total motile sperm of 5 million to 16 million, such as 5 million to 10 million, such as 6 million to 8 million; sperm count; ≥15% of sperm with normal morphology (oval head, intact midpiece, and uncoiled single tail, and able to swim well and in a straight manner (e.g., forward propulsion / anterior motion)); baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L; baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L; baseline serum hormone concentration of testosterone of ≥300 ng / dL (equivalent to ≥10.4 nmol / L).

[0074] The aforementioned parameters can be assessed by methods known in the art, such as those according to World Health Organization (WHO) criteria. See, for example, Boitrelle et al., Life (2021) 11(12): 1368. The assessment of semen and sperm parameters can be performed by manual semen evaluation performed in the laboratory, optionally including computer-assisted sperm analysis. Additionally or alternatively, the assessment of sperm parameters can include the use of a sperm testing device, such as Device (ExSeedHealth, Denmark), or other sperm testing devices, such as those reviewed in Onofre et al., Facts Views Vis ObGyn [Facts, Views and Visions in Obstetrics and Gynecology] (2021) 13(1):79-93. Parameters related to semen and sperm characteristics can be evaluated and confirmed in one sample or in multiple samples collected at the same or different times, such as at the time of initial screening for treatment and then closer to the time of treatment initiation, such as at the time of initial screening for treatment and in two consecutive samples collected within about 90 days of treatment initiation (e.g., ≥2 weeks before treatment initiation, but within about 90 days of treatment initiation).

[0075] In some aspects, the patient has not undergone FSH treatment and will not conceive with his partner. Additionally or alternatively, in some aspects, the patient has not undergone administration of hormone preparations within 3 months prior to screening.

[0076] According to all aspects described herein, the recombinant human follicle stimulating hormone (rFSH) comprising α2,3- and α2,6-sialylation may be a recombinant FSH derived from a human cell line, as described in more detail below. In all aspects, the recombinant FSH comprising α2,3- and α2,6-sialylation may be a recombinant FSH obtained under the trademark (Follitropin delta) (sold by Ferring BV). In all aspects, recombinant FSH may be administered by injection, for example subcutaneously.

[0077] treat

[0078] In a proof-of-concept (PoC) trial described below, the inventors demonstrated that the chances of spontaneous pregnancy in female partners of men with idiopathic infertility were improved following treatment with a daily dose of 11-13 μg FE 999049 (e.g., 12 μg FE 999049) compared to men treated with placebo.

[0079] The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or in reducing seminal DNA fragmentation of sperm / semen of treated male patients. For example, the treatment may be effective in increasing total sperm count or total motile sperm count by 50% or more over baseline.

[0080] The treatment may also be effective in increasing the chance of a positive beta-human chorionic gonadotropin (βhCG) urine test in the female partner of the treated subject compared to males treated with placebo. The treatment may also be effective in reducing the time to spontaneous pregnancy (as can be assessed, for example, by one or more of calendar time and number of menstrual cycles) in the female partner of the treated subject compared to males treated with placebo.

[0081] As described above, the therapeutic effect can be observed after 28 or 30 days to 6 months of treatment. In addition, the patient's therapeutic benefit can continue for a period of time after the treatment stops, for example, three months or more after the end of treatment.

[0082] The inventors believe that the results of this trial will demonstrate that a daily dose of 11-13 μg FE 999049 (e.g., 12 μg FE 999049) will provide significantly greater FSH exposure levels (as measured by AUC and C maxThe present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency. The present invention also provides a method for evaluating the efficacy of FE999049 in treating patients with FSH deficiency.

[0083] Therefore, the inventors believe that the dosing regimen described herein will increase the chance of spontaneous pregnancy observed in the female partner of the treated male patient compared to patients treated with a placebo (inactive treatment). The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or effectively reduce the seminal DNA fragmentation of the sperm / sperm of the treated male patient. Compared to men treated with a placebo, the treatment may also be effective in increasing the chance of positive β-human chorionic gonadotropin (βhCG) urine tests in the female partner of the treated subject. Compared to men treated with a placebo, the treatment may also be effective in reducing the time to spontaneous pregnancy (as may be assessed, for example, by one or more of calendar time and menstrual cycle number) in the female partner of the treated subject.

[0084] Therapeutic Compositions

[0085] In a first aspect, a composition (e.g., a pharmaceutical composition) comprising rFSH is provided for use in treating idiopathic infertility in a male patient, wherein the rFSH comprises α2,3-sialylated and α2,6-sialylated (e.g., follitropin delta), wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0086] The infertility may be at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, spermatopenia, and sperm abnormality.

[0087] The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 80% to 90% of the total sialylation is α2,3-sialylation, and wherein 10% to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta, available from Ferring Pharmaceuticals). The rFSH may be in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase rFSH produced or expressed in cell lines. The cell line has been deposited at the European Collection of Certified Cell Cultures on February 29, 1996 under ECACC accession number 96022940.

[0088] As described above, in some aspects, this is applied to the patient with a daily dose of 11-13 μg (e.g., 12 μg) for a treatment period of at least 28 days (e.g., a medical month). In some aspects, this is applied to the patient with a daily dose of 11-13 μg (e.g., 12 μg) for a treatment period of at least 30 days. In some aspects, this is applied to the patient with a daily dose of 11-13 μg (e.g., 12 μg) for a treatment period of 28 days to 6 months. In some aspects, this is applied to the patient with a daily dose of 11-13 μg (e.g., 12 μg) for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 4 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 5 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 6 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue at least six months of treatment period (comprising the treatment period that continues at least one year). It will be understood that this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply rFSH to this patient and may need longer time period, up to 18 months, for example, to realize spermatogenesis. On the other hand, the therapeutic benefit of patient can continue for a period of time after treatment stops, so shorter treatment period can be effective.

[0089] The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0090] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0091] In a second aspect, a composition (e.g., a pharmaceutical composition) comprising rFSH is provided for use in treating infertility in a male patient, wherein the rFSH comprises α2,3-sialylated and α2,6-sialylated (e.g., follitropin delta), wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0092] The infertility may be at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, spermatopenia, and sperm abnormality.

[0093] The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 80% to 90% of the total sialylation is α2,3-sialylation, and wherein 10% to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta, available from Ferring Pharmaceuticals). The rFSH may be in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase rFSH produced or expressed in cell lines.

[0094] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 4 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 5 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 6 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue at least six months of treatment period (comprising the treatment period that continues at least one year). It will be understood that this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply rFSH to this patient and may need longer time period, up to 18 months, for example, to realize spermatogenesis. On the other hand, the therapeutic benefit of patient can continue for a period of time after treatment stops, so shorter treatment period can be effective.

[0095] The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0096] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0097] In a further aspect, a composition (e.g., a pharmaceutical composition) comprising rFSH is provided for use in treating male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylated and α2,6-sialylated (e.g., follitropin delta), wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0098] The infertility may be at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, spermatopenia, and sperm abnormality.

[0099] The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 80% to 90% of the total sialylation is α2,3-sialylation, and wherein 10% to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta, available from Ferring Pharmaceuticals). The rFSH may be in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase rFSH produced or expressed in cell lines. The cell line has been deposited at the European Collection of Certified Cell Cultures on February 29, 1996 under ECACC accession number 96022940.

[0100] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 4 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 5 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 6 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue at least six months of treatment period (comprising the treatment period that continues at least one year). It will be understood that this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply rFSH to this patient and may need longer time period, up to 18 months, for example, to realize spermatogenesis. On the other hand, the therapeutic benefit of patient can continue for a period of time after treatment stops, so shorter treatment period can be effective.

[0101] The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). As used herein, a "baseline" value refers to a value before treatment as described herein. In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0102] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0103] In a further aspect, a composition (e.g., a pharmaceutical composition) comprising rFSH is provided for use in treating testosterone deficiency in a male patient, wherein the rFSH comprises α2,3-sialylated and α2,6-sialylated (e.g., follitropin delta), wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0104] The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 80% to 90% of the total sialylation is α2,3-sialylation, and wherein 10% to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta, available from Ferring Pharmaceuticals). The rFSH may be in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase rFSH produced or expressed in cell lines. The cell line has been deposited at the European Collection of Certified Cell Cultures on February 29, 1996 under ECACC accession number 96022940.

[0105] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 4 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 5 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 6 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue at least six months of treatment period (comprising the treatment period that continues at least one year). It will be understood that this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply rFSH to this patient and may need longer time period, up to 18 months, for example, to realize spermatogenesis. On the other hand, the therapeutic benefit of patient can continue for a period of time after treatment stops, so shorter treatment period can be effective.

[0106] The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0107] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0108] In a further aspect, a composition (e.g., a pharmaceutical composition) comprising rFSH is provided for use in treating idiopathic oligospermia in a male patient, wherein the rFSH comprises α2,3-sialylated and α2,6-sialylated (e.g., follitropin delta), wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0109] The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. The rFSH may include α2,3-sialylation and α2,6-sialylation, wherein 80% to 90% of the total sialylation is α2,3-sialylation, and wherein 10% to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta, available from Ferring Pharmaceuticals). The rFSH may be in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase rFSH produced or expressed in cell lines. The cell line has been deposited at the European Collection of Certified Cell Cultures on February 29, 1996 under ECACC accession number 96022940.

[0110] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 4 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 5 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 6 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue at least six months of treatment period (comprising the treatment period that continues at least one year). It will be understood that this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply rFSH to this patient and may need longer time period, up to 18 months, for example, to realize spermatogenesis. On the other hand, the therapeutic benefit of patient can continue for a period of time after treatment stops, so shorter treatment period can be effective.

[0111] The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0112] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0113] Treatment

[0114] In a further aspect, methods for treating infertility in male patients are provided, comprising administering to the patient rFSH comprising α2,3-sialylated and α2,6-sialylated, wherein the rFSH is administered at a dosage of 11-13 μg (e.g., 12 μg) / day. As described above, the rFSH can be administered by injection, such as subcutaneous injection.

[0115] The treatment of infertility may be the treatment of idiopathic infertility. The treatment of infertility may be the treatment of male factor infertility. The infertility may be one or more sperm-related infertility disorders selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, spermatopenia, and sperm abnormalities.

[0116] In a further aspect, methods for treating male testosterone deficiency are provided, comprising administering to a male patient rFSH comprising α2,3-sialylated and α2,6-sialylated, wherein the rFSH is administered at a dosage of 11-13 μg (e.g., 12 μg) / day. As described above, the rFSH can be administered by injection, e.g., subcutaneous injection.

[0117] In a further aspect, a method for treating idiopathic oligospermia in a male patient is provided, the methods comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dosage of 11-13 μg (e.g., 12 μg) / day. As described above, the rFSH can be administered by injection, e.g., subcutaneous injection.

[0118] In any of these treatment methods, the rFSH can include α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation. The rFSH can include α2,3-sialylation and α2,6-sialylation, wherein 80% to 90% of the total sialylation is α2,3-sialylation, and wherein 10% to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta, available from Ferring Pharmaceuticals). The rFSH can be in a human cell line, such as Cell lines, such as those that have been modified with α2,3-sialyltransferase rFSH produced or expressed in cell lines. The cell line has been deposited at the European Collection of Certified Cell Cultures on February 29, 1996 under ECACC accession number 96022940.

[0119] In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 28 days (e.g., a medical month). In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of at least 30 days. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 28 days to 6 months. In some aspects, the daily dosage of 11-13 μg (e.g., 12 μg) is used to the patient for a treatment period of 30 days to 6 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for a treatment period selected from the following: 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks and 6 months or longer. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 28 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 30 days. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 2 months. In some aspects, the daily dosage of 11-13 μ g (for example, 12 μ g) is used to the patient for 3 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 4 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 5 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue 6 months. In some aspects, this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply to this patient and continue at least six months of treatment period (comprising the treatment period that continues at least one year). It will be understood that this with the daily dosage of 11-13 μ g (for example, 12 μ g) to apply rFSH to this patient and may need longer time period, up to 18 months, for example, to realize spermatogenesis. On the other hand, the therapeutic benefit of patient can continue for a period of time after treatment stops, so shorter treatment period can be effective.

[0120] In some aspects, the patient has one or more of the following characteristics prior to treatment, e.g., at the start of treatment or within about 90 days of starting treatment. The patient may have a ≤35 kg / m 2The patient may have a body mass index (BMI) of ≥1.4 mL of semen volume. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of less than or equal to 3 million sperm / mL, for example, less than or equal to 2 million sperm / mL, for example, less than or equal to 1 million sperm / mL, for example, less than or equal to 500,000 sperm / mL. The patient may have a total active sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥15% of sperm with normal morphology (oval head, complete midsection and uncoiled single tail, and able to swim well and in a straight line). The patient may have a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equal to ≥10.4 nmol / L). In some aspects, the patient has not undergone FSH treatment and will not conceive his partner. Additionally or alternatively, in some aspects, the patient has not undergone the use of hormone preparations within 3 months before screening.

[0121] According to some aspects, compared with placebo, the treatment is effective to improve the chance of spontaneous pregnancy observed in the female partner of treated male patients. According to some aspects, the treatment is effective to improve one or more or all of seminal fluid volume, sperm concentration, total sperm count, sperm motility and sperm morphology, or effectively reduce the seminal DNA fragmentation of sperm / sperm of treated male patients. According to some aspects, compared with males treated with placebo, the treatment is effective to improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of treated subjects. In some aspects, compared with males treated with placebo, the treatment is effective to reduce the time to spontaneous pregnancy of the female partner of treated subjects (as can be assessed, for example, by one or more of calendar time and menstrual cycle number).

[0122] Recombinant FSH and rFSH Combinations

[0123] The methods and compositions described herein use recombinant FSH (rFSH) including α2,3-sialylated and α2,6-sialylated. FSH comprises a 92 amino acid α subunit (also a common subunit of other glycoprotein hormones LH and chorionic gonadotropin (CG)), and a 111 amino acid β subunit unique to FSH (which confers the biological specificity of the hormone). Each subunit is post-translationally modified by the addition of complex carbohydrate residues. Both subunits carry 2 N-linked glycan attachment sites, the α subunit at amino acids 52 and 78 and the β subunit at amino acid residues 7 and 24. Thus, FSH is glycosylated to about 30% by mass.

[0124] The glycosylation of a given rFSH product reflects the range of glycosyltransferases present in the host cell line. Commercially available rFSH products derived from engineered CHO cells have a more limited range of glycan modifications than those found in natural human products. Examples of reduced glycan heterogeneity found in CHO cell-derived rFSH include the lack of bisected glucosamine and the reduction in the content of core fucosylation and acetyllactosamine extensions. In addition, CHO cells are only able to add sialic acid using α2,3-bonds; CHO cell-derived rFSH only includes α2,3-linked sialic acids and does not include α2,6-linked sialic acids. Therefore, CHO cell-derived rFSH is different from naturally produced human FSH (e.g., human pituitary / serum / urinary FSH), which contains glycans with a mixture of α2,3- and α2,6-linked sialic acids (where the former is dominant).

[0125] As mentioned above, the applicants have developed human cell line derived rFSH which is the subject of international patent application number PCT / GB 2009 / 000978 published as WO 2009 / 127826A and which was also approved by the EC as (Follitropin δ, also known as FE 999049). Recombinant FSH with a mixture of α2,3- and α2,6-linked sialic acids was prepared by engineering a human cell line to express rFSH and α2,3-sialyltransferase. The amino acid sequence of recombinant FSH derived from a human cell line (which is the subject of international patent application number PCT / GB2009 / 000978 published as WO 2009 / 127826 A) (e.g., FE 999049 / Follitropin δ) is identical to the sequence of natural human FSH, but FE 999049 has a different glycosylation pattern. The recombinantly expressed product is highly acidic and carries a mixture of α2,3- and α2,6-linked sialic acids; the latter is provided by endogenous sialyltransferase activity. It was found that the type of sialic acid bond α2,3- or α2,6- has a significant effect on the biological clearance of FSH. Therefore, compared with CHO cell-derived recombinant products that have only α2,3-linked sialic acid and have reduced sialic acid content, (e.g., FE 999049) may be more biologically suitable (and more biologically active).

[0126] Thus, recombinant FSH including α2,3-sialylated and α2,6-sialylated FSH used in accordance with the methods and compositions described herein can be expressed in human cell lines such as As described above, The cell line has been deposited with the European Collection of Certified Cell Cultures on February 29, 1996 under the ECACC accession number 96022940. Recombinant FSH can be obtained from Cell lines, Derived cell lines or modified Produced or expressed in cell lines. Recombinant FSH produced or expressed in a cell line will include some α2,6-linked sialic acid (α2,6 sialylation) provided by the endogenous 2,6-sialyltransferase activity (of the cell line), and will include some α2,3-linked sialic acid (α2,3 sialylation) provided by the endogenous α2,3-sialyltransferase activity. The cell line can be modified using an α2,3-sialyltransferase (e.g., to increase the amount of α2,3 sialylation on the product rFSH). The cell line can be modified using an α2,6-sialyltransferase (e.g., to increase the amount of α2,6 sialylation on the product rFSH). Alternatively or in addition, recombinant FSH may include α2,6-linked sialic acid (α2,6 sialylation) provided by the endogenous sialyltransferase activity (of the cell line).

[0127] The recombinant FSH used in the methods and compositions described herein may include α2,3- and α2,6-sialylation. The recombinant FSH used according to the present invention may have 1% to 99% of total sialylation as α2,3-sialylation. The recombinant FSH used according to the present invention may have 1% to 99% of total sialylation as α2,6-sialylation. The recombinant FSH may have 1% to 50% of total sialylation as α2,6-sialylation, and 50% to 99% of total sialylation as 2,3-sialylation. For example, 80% to 95% (e.g., 80% to 90%, e.g., 82% to 89%, e.g., 85% to 89%) of the total sialylation may be α2,3-sialylation. For example, 5% to 20% (e.g., 10% to 20%, e.g., 11% to 18%, e.g., 11% to 15%) of the total sialylation may be α2,6-sialylation. In an example, the recombinant FSH has 5% to 20% of the total sialylation as α2,6-sialylation, and 80% to 95% of the total sialylation as 2,3-sialylation. In another example, the recombinant FSH has 50% to 80% of the total sialylation as α2,6-sialylation, and 20% to 50% of the total sialylation as 2,3-sialylation.

[0128] In this article, "sialylation", it means the amount of sialic acid residues present on the recombinant FSH carbohydrate structure. Consistent with the usage in the art, α2,3-sialylation means sialylation at the 2,3 position and α2,6 sialylation means sialylation at the 2,6 position. Therefore, "% of total sialylation can be α2,3 sialylation" refers to the total number of sialic acid residues present in FSH sialylated at the 2,3 position. The term "% of total sialylation is α2,6-sialylation" refers to the total number of sialic acid residues present in FSH sialylated at the 2,6 position.

[0129] In all aspects, rFSH may be present as a single isoform or as a mixture of isoforms.

[0130] The composition can be a pharmaceutical composition. The pharmaceutical composition is used to treat infertility.

[0131] The recombinant FSH, composition or pharmaceutical composition can be formulated into well-known compositions for any route of drug administration and is typically formulated for subcutaneous injection and administered by subcutaneous injection. Typical compositions contain pharmaceutically acceptable carriers such as aqueous solutions, non-toxic excipients (including salts and preservatives, buffers, etc.), as described in Remington’s Pharmaceutical Sciences, Fifteenth Edition (Matt Publishing Company, 1975), pages 1405 to 1412 and 1461 - 87, and the fourteenth edition of the national formulary XIV (American Pharmaceutical Association, 1975), etc. For example, the recombinant FSH, composition or pharmaceutical composition can be formulated for injection, such as for subcutaneous injection.

[0132] Examples of suitable aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate).

[0133] The compositions of the present invention may also contain additives such as, but not limited to, preservatives, wetting agents, emulsifying agents, surfactants and dispersants. Antibacterial and antifungal agents may be included to prevent microbial growth and include, for example, m-cresol, benzyl alcohol, parabens, chlorobutanol, phenol, sorbic acid, etc. If a preservative is included, benzyl alcohol, phenol and / or m-cresol are preferred; however, the preservatives are by no means limited to these examples. In addition, it may be desirable to include isotonic agents such as sugars, sodium chloride, amino acids, etc.

[0134] The pH and the precise concentration of the various components of the pharmaceutical composition are adjusted according to conventional practice in the art. Referring to GOODMAN and GILMAN's THE PHARMACOLOGICAL BASIS FOR THERAPEUTICES [Pharmacological Basis for Treatment], the 7th edition. In a typical embodiment, recombinant FSH, compositions or medicines are provided as compositions for parenteral administration (e.g., by subcutaneous injection). The general method for preparing parenteral formulations (including formulations for use by subcutaneous injection) is known in the art and is described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY [Pharmacy Science and Practice], the same, pp. 780-820. These compositions can be provided in liquid formulation form or as solid, which will be mixed with a sterile injectable medium just before administration. These compositions can be provided in dosage unit form to be easy to use and to achieve dosage uniformity.

[0135] For example, the composition or drug may comprise recombinant FSH and one or more of polysorbate 20, L-methionine, phenol and arginine hydrochloride. Such a composition may be formulated for injection, such as for subcutaneous injection. For example, the composition or drug may be Formulation (including α2,3- and α2,6-sialylated rFSH with excipients phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, sodium phosphate dibasic dodecahydrate, phosphoric acid [concentrated, for pH adjustment], sodium hydroxide [for pH adjustment] and water for injection).

[0136] Injectable formulations can be sterilized, for example, by filtration through a bacterial barrier filter, or by incorporating sterilizing agents in the form of sterile solid compositions (which can be dissolved or dispersed in sterile water or other sterile injectable media prior to use). Injectable formulations can be provided in any suitable container (e.g., vials, prefilled syringes, injection boxes, etc.).

[0137] Recombinant FSH, compositions or medicine can be formulated for single use or for multiple use (multiple doses). If recombinant FSH, compositions or medicine are formulated for multiple use, one or more preservatives are typically included. If preservatives are included, benzyl alcohol, phenol or meta-cresol are preferred; However, preservatives are by no means limited to these examples. The single use or multiple use compositions or medicines prepared can further include amino acids or amino acid combinations. Typically, the amino acid is arginine, for example, is added as arginine or more typically arginine hydrochloride.

[0138] Recombinant FSH, compositions or medicine can be included in a container, such as a vial, a pre-filled cartridge (e.g., for single administration or multiple use) or an injection device (such as a "pen", for example, for multiple doses). Recombinant FSH, compositions or medicine can be provided in a container (e.g., using a "pen"), which is designed to deliver one or more dosages described herein, such as one or more predetermined doses of 11-13 μg (e.g., 12 μg) rFSH. For example, a pre-filled cartridge or pen can contain one or more predetermined doses of 11-13 μg (e.g., 12 μg) rFSH.

[0139] The recombinant FSH, composition or pharmaceutical composition may be a formulation (eg, an injectable formulation) comprising rFSH.

[0140] Recombinant FSH, compositions or medicine can be provided with any suitable packaging.For example, compositions or medicine can include multiple containers (for example, pre-filled syringes or vials) containing rFSH.Syringes or vials can be packaged in blister packs or keep sterile by other means.Any compositions or medicine can optionally include instructions for use of FSH preparations.

[0141] In a further aspect, there is provided use of a recombinant follicle stimulating hormone (FSH) comprising α2,3- and α2,6-sialylation in the manufacture of a medicament for use as described herein.

[0142] Further aspects are demonstrated in the following examples, which are not limiting in any respect.

[0143] Example

[0144] The following example uses (Follitropin delta), which is in The recombinant FSH expressed in the cell line includes α2,3- and α2,6-sialylated FSH, the cell line being engineered by the methods disclosed in WO 2013 / 020996 and WO 2009 / 127826A.

[0145] The marketing authorisation holder for is Ferring Pharmaceuticals A / S, KayFiskers Plads 11, 2300 Copenhagen, Denmark, and in the UK, Available from Ferring Pharmaceuticals, Drayton Hall, Church Road, West Drayton, UB7 7PS, UK.

[0146] The active substance in is follitropin delta (FE999049). is highly sialylated and includes α2,3- and α2,6-sialylation, with about 85% to 90% of the total sialylation being α2,3-sialylation and about 10% to 15% of the total sialylation being α2,6-sialylation.

[0147] It is a transparent colorless solution for injection (injection). 1 mL of solution contains 33.3 micrograms of follitropin delta in each mL of solution. The other ingredients are phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium hydrogen phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide and water for injection.

[0148] Example 1: Trial comparing the efficacy and safety of follitropin delta versus placebo (inactive treatment) in the treatment of men with idiopathic infertility (unexplained reduction in sperm quality) (ADAM)

[0149] introduce

[0150] The ADAM trial will study whether the chance of spontaneous pregnancy of the female partner of a male with idiopathic infertility after 6 months of treatment with 12 μg daily dose of recombinant follicle stimulating hormone (rFSH) compared with a male treated with a placebo (inactive treatment) is improved. The therapeutic benefit of the patient can last for a period of time after the treatment stops, so the trial will track the results after the end of the 6-month study treatment, i.e., track 3 months after the end of the treatment. As mentioned above, the therapeutic effect can be observed in a shorter period of time, such as 30 days or one month. The treatment can also effectively improve one or more or all of the semen volume, sperm concentration, total sperm count, sperm movement, and sperm morphology, or effectively reduce the seminal DNA fragmentation of the sperm / sperm of the treated male patient. Compared with the male treated with a placebo (inactive treatment), the treatment can also effectively improve the chance of positive β-human chorionic gonadotropin (βhCG) urine test of the female partner of the treated subject. The treatment may also be effective in reducing the time to spontaneous pregnancy (as can be assessed by one or more of calendar time and number of menstrual cycles) of the female partner of the treated subject compared to males treated with placebo. The treatment may also be effective in increasing the chance of a positive beta-human chorionic gonadotropin (βhCG) urine test of the female partner of the treated subject compared to males treated with placebo. The treatment may also be effective in reducing the time to spontaneous pregnancy (as can be assessed, for example, by one or more of calendar time and number of menstrual cycles) of the female partner of the treated subject compared to males treated with placebo.

[0151] method

[0152] This is a randomized, double-blind, placebo-controlled, multi-regional trial evaluating the efficacy and safety of FE 999049 in men with idiopathic infertility. Patients will be recruited at approximately 25 sites in approximately 7 countries across Europe and North America. All participants will sign written informed consent before undergoing any study-related procedures.

[0153] Study participants

[0154] 400 men aged 18-50 years (inclusive) with a 12-60 month history of infertility and their current partners are planned to be recruited. Their current partners must be premenopausal women aged 18-35 years with no contraindications to pregnancy, with regular menstrual cycles of 21-35 days, and with no history or current condition of pelvic inflammatory disease.

[0155] The absence of stage II-IV endometriosis, as determined or empirically diagnosed, or tubal ligation.

[0156] Additional inclusion criteria for male subjects was a body mass index (BMI) ≤ 35 kg / m 2 , total sperm count at screening of 5 million-39 million (and confirmed by two consecutive samples collected ≥2 weeks before randomization), total motile sperm count at screening of 5 million-16 million (and confirmed by two consecutive samples collected ≥2 weeks before randomization), semen volume ≥1.4mL at screening (and confirmed by two consecutive samples collected ≥2 weeks before randomization), serum follicle stimulating hormone (FSH) level at screening of 1.5-8.0IU / L, serum luteinizing hormone (LH) level at screening of 1.2-7.5IU / L, serum total testosterone level ≥300ng / dL (equal to ≥10.4nmol / L) at screening. Exclusion criteria included previous FSH treatment that did not result in conception and administration of hormonal preparations within 3 months before screening. The first man was recruited in August 2022, and 400 people were randomized at sites in the United States and European countries.

[0157] Study Procedure

[0158] Subjects will be screened within 90 days prior to randomization to meet inclusion and exclusion criteria.Approximately 200 participants will be randomized to receive once daily subcutaneous administration of 12 μg FE 999049, and approximately 200 participants will be randomized to receive placebo treatment (Table 1).

[0159] Table 1: Investigational Medicinal Products (IMPs) in the ADAM Trial

[0160]

[0161] All randomized subjects will continue treatment for 6 months and be followed up for an additional 3 months. 6 months was chosen as the duration of treatment to ensure that subjects are exposed to FE 999049 during at least two complete spermatogenic cycles, allowing for a thorough evaluation of the therapeutic potential of FE999049. Subjects will remain in the trial for 9 months regardless of whether a spontaneous pregnancy is established at an earlier time point. Subjects will also remain in the trial if the couple experiences a pregnancy loss.

[0162] In addition to partner pregnancy outcomes, semen parameters (e.g., semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology, and DNA fragmentation) and other male patient parameters (e.g., changes in serum hormone concentrations (e.g., FSH, LH, inhibin B, testosterone, estradiol) and changes in free testosterone concentrations) will be measured and analyzed. Semen and sperm parameters will be assessed by methods known in the art, such as those according to World Health Organization (WHO) criteria. See, e.g., Boitrelle et al., Life (2021). In addition, subjects can use sperm testing devices to assess their own sperm parameters, such as device (ExSeed Health, Denmark), or other sperm testing devices such as those reviewed in Onofre et al., Facts Views Vis ObGyn (2021) 13(1):79-93.

[0163] All cases of spontaneous pregnancy in the female partner occurring within 9 months of the male subject's randomization date will be followed during pregnancy to collect information on pregnancy loss and live birth. In addition, data on minor / major congenital anomalies in the newborn will be collected at birth, 4 weeks and 1 year after birth.

[0164] Study Results

[0165] The primary endpoint of the study was the observation of spontaneous pregnancy in the female partner within 9 months after the male subject started treatment, where spontaneous pregnancy was defined as a life pregnancy (at least one intrauterine gestational sac with a fetal heartbeat recorded by ultrasound). Secondary objectives were positive urine βhCG in the female partner, time to spontaneous pregnancy, changes in semen parameters (e.g., semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology, and semen DNA fragmentation), changes in serum hormone concentrations (e.g., FSH, LH, inhibin B, testosterone, estradiol), and changes in free testosterone concentrations, thereby objectively measuring the effects of FE 999049 treatment on male subjects. Safety was assessed by evaluating blood samples to assess anti-FSH antibodies and identify immune-related adverse events.

[0166] result

[0167] The ADAM study will be the first study to use FE 999049 (follicle stimulating hormone delta) to treat idiopathic infertility in male patients. The inventors believe that a daily dose of 12 μg FE 999049 (which is rFSH including α2,3-sialylation and α2,6-sialylation) will be safe and well tolerated in the patient population described herein. In addition, the inventors believe that a high daily dose of 12 μg FE 999049 (including rFSH with α2,3-sialylation and α2,6-sialylation) will provide significantly greater (e.g., as measured by AUC and C max measured) and more consistent FSH exposure.

[0168] It is expected that increasing the FSH dosage (see, for example, Ding and Cannarella mentioned in the above 2nd page) better indicates the maximum possible therapeutic effect on spontaneous pregnancy rate and semen parameters compared with previous studies. The trial population is carefully defined to include men diagnosed with unknown infertility (including oligoasthenozoospermia), which is consistent with the possible benefits of FSH treatment. The primary endpoint is to observe spontaneous life pregnancy in female partners within 9 months after the male subject is randomized, and the secondary endpoint includes the change of semen parameters. The Bayesian framework for decision-making in the presence of a single target therapeutic effect will be used, and the framework is defined as making the efficacy above this target interesting. The trial is intended to prove that when comparing FE999049 and placebo treatment groups, the spontaneous pregnancy rate increases by at least 10%. The proof-of-concept conclusion will be based on the primary endpoint of the evidence that statistical significance and clinical relevance are demonstrated using Bayesian decision criteria.

[0169] The inventors believe that the therapeutic compositions and methods described herein will increase the spontaneous pregnancy rate by 10% when comparing the FE 999049 treatment group to the placebo treatment group; this increase is clinically significant. Therefore, the inventors believe that the dosing regimen described herein will increase the chance of observing spontaneous pregnancy in the female partners of treated subjects compared to placebo (inactive treatment).

[0170] The products, products for use, uses and methods defined by the following numbered paragraphs have been disclosed above (recombinant FSH, recombinant FSH products, pharmaceutical compositions, uses and methods):

[0171] 1. A composition comprising rFSH for use in treating idiopathic infertility in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0172] 2. A composition comprising rFSH for use in treating infertility in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0173] 3. A composition comprising rFSH for use in treating male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0174] 4. The composition for use according to paragraph 1, 2 or 3, wherein the infertility is at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, sperm cell reduction and sperm abnormality.

[0175] 5. A composition for use according to any preceding paragraph, wherein 5% to 20% of the total sialylation is α2,6-sialylation and / or wherein the rFSH may be in produced or expressed in a cell line.

[0176] 6. A composition for use according to any preceding paragraph, wherein the daily dose of 11-13 μg (e.g., 12 μg) is administered to the patient for a treatment period selected from: (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks, (xx) 24 weeks, and (xxi) 6 months.

[0177] 7. A composition for use according to any preceding paragraph, wherein the patient has a 2 body mass index (BMI).

[0178] 8. A composition for use according to any preceding paragraph, wherein the patient has a semen volume ≥ 1.4 mL.

[0179] 9. A composition for use according to any preceding paragraph, wherein the patient has a baseline total sperm count of 5 million to 39 million.

[0180] 10. A composition for use according to any preceding paragraph, wherein the patient has a sperm concentration of less than 5 million sperm / mL.

[0181] 11. A composition for use according to any preceding paragraph, wherein the patient has a sperm concentration of less than or equal to 3 million sperm / mL, such as less than or equal to 2 million sperm / mL, such as less than or equal to 1 million sperm / mL, such as less than or equal to 500,000 sperm / mL.

[0182] 12. A composition for use according to any preceding paragraph, wherein the patient has a total motile sperm count of 5 to 16 million.

[0183] 13. A composition for use according to any preceding paragraph, wherein the patient has ≥15% sperm with normal morphology (oval head, intact midpiece and uncoiled single tail, and able to swim well and in a straight manner).

[0184] 14. A composition for use according to any preceding paragraph, wherein the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L.

[0185] 15. A composition for use according to any preceding paragraph, wherein the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L.

[0186] 16. A composition for use according to any preceding paragraph, wherein the patient has a baseline serum hormone concentration of testosterone of ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L).

[0187] 17. A composition comprising rFSH for use in treating testosterone deficiency in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0188] 18. A composition comprising rFSH for use in treating idiopathic oligospermia in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0189] 19. A method for treating infertility in a male patient, the method comprising:

[0190] The patient is administered rFSH comprising α2,3-sialylated and α2,6-sialylated, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day.

[0191] 20. The method according to paragraph 19, wherein the infertility is male factor infertility.

[0192] 21. The method according to paragraph 19, wherein the infertility is idiopathic infertility.

[0193] 22. The method according to paragraph 19, wherein the infertility is at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, spermatopenia and sperm abnormality.

[0194] 23. A method of treating testosterone deficiency in a male patient, the method comprising administering to the patient rFSH comprising α2,3-sialylated and α2,6-sialylated, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day.

[0195] 24. A method of treating idiopathic oligospermia in a male patient, the method comprising administering to the patient rFSH comprising α2,3-sialylated and α2,6-sialylated, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day.

[0196] 25. The method according to any of paragraphs 19-24, wherein 5% to 20% of the total sialylation of the rFSH is α2,6-sialylation.

[0197] 26. The method according to any one of paragraphs 19-25, wherein the rFSH is produced or expressed in a cell line.

[0198] 27. The method according to any one of paragraphs 19-26, wherein the method comprises administering the rFSH to the patient at a daily dose of 11-13 μg for a treatment period selected from: (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks, (xx) 24 weeks, and (xxi) 6 months.

[0199] 28. The method according to any one of paragraphs 19-27, wherein the patient has one or more or all of the following characteristics before treatment:

[0200] Body mass index (BMI) ≤ 35 kg / m 2 ;

[0201] Semen volume ≥1.4 mL;

[0202] Total sperm count of 5 to 39 million;

[0203] Sperm concentration of less than 5 million sperm / mL;

[0204] Sperm concentration less than or equal to 3 million sperm / mL;

[0205] Total motile sperm count of 5 to 16 million;

[0206] ≥15% sperm with normal morphology;

[0207] serum concentrations of follicle-stimulating hormone (FSH) of 1.5 to 8.0 IU / L;

[0208] serum concentrations of luteinizing hormone (LH) of 1.2 to 7.5 IU / L;

[0209] A serum concentration of testosterone ≥300 ng / dL (≥10.4 nmol / L).

[0210] 29. The method of any of paragraphs 19-28, wherein the patient has a sperm concentration selected from the group consisting of less than 5 million sperm / mL, less than 4 million sperm / mL, less than or equal to 3 million sperm / mL, less than or equal to 2 million sperm / mL, less than or equal to 1 million sperm / mL, and less than or equal to 500,000 sperm / mL.

[0211] 30. The method according to any of paragraphs 19-29, wherein the method is effective to increase the chance of spontaneous pregnancy in the female partner of the treated male patient.

[0212] 31. The method of any one of paragraphs 19-30, wherein the method is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or is effective in reducing seminal DNA fragmentation in the sperm / semen of the treated male patient.

[0213] 32. The method of any of paragraphs 19-31, wherein the method is effective to increase the chance of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partner of the treated subject compared to males treated with placebo.

[0214] 33. The method of any of paragraphs 19-32, wherein the method is effective to reduce the time to spontaneous pregnancy in the female partner of the treated subject compared to males treated with placebo.

Claims

1. A composition comprising rFSH for use in treating idiopathic infertility in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 12-13 μg (e.g., 12 μg).

2. A composition comprising rFSH for use in treating infertility in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 12-13 μg (e.g., 12 μg).

3. A composition comprising rFSH for use in treating male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, wherein the rFSH is for administration to the patient at a daily dose of 12-13 μg (e.g., 12 μg).

4. The composition for use according to claim 1, 2 or 3, wherein the infertility is at least one sperm-related infertility selected from the group consisting of azoospermia, oligospermia, asthenozoospermia, teratozoospermia, microspermia, sperm cell reduction and sperm abnormality.

5. A composition for use according to any preceding claim, wherein 5% to 20% of the total sialylation is α2,6-sialylation and / or wherein the rFSH is produced or expressed in a cell line.

6. A composition for use according to any preceding claim, wherein the daily dose of 12-13 μg (e.g., 12 μg) is administered to the patient for a treatment period selected from: (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks, (xx) 24 weeks, and (xxi) 6 months.

7. A composition for use according to any preceding claim, wherein the patient has a 2 body mass index (BMI).

8. A composition for use according to any preceding claim, wherein the patient has a semen volume of ≥ 1.4 mL.

9. A composition for use according to any preceding claim, wherein the patient has a baseline total sperm count of 5 to 39 million.

10. A composition for use according to any preceding claim, wherein the patient has a sperm concentration of less than 5 million sperm / mL.

11. A composition for use according to any preceding claim, wherein the patient has a sperm concentration of less than or equal to 3 million sperm / mL, such as less than or equal to 2 million sperm / mL, such as less than or equal to 1 million sperm / mL, such as less than or equal to 500 000 sperm / mL.

12. A composition for use according to any preceding claim, wherein the patient has a total motile sperm count of 5 to 16 million.

13. A composition for use according to any preceding claim, wherein the patient has ≥15% of sperm with normal morphology (oval head, intact midpiece and uncoiled single tail, and able to swim well and in a straight line), and / or wherein the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 to 8.0 IU / L, and / or wherein the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L, and / or wherein the patient has a baseline serum hormone concentration of testosterone of ≥300 ng / dL (equivalent to ≥10.4 nmol / L).

14. A composition comprising rFSH for use in treating testosterone deficiency in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is for administration to the patient at a daily dose of 11-13 μg (e.g., 12 μg).

15. A composition comprising rFSH for use in treating idiopathic oligospermia in a male patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is for administration to the patient at a daily dose of 12-13 μg (e.g., 12 μg).

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